Development programme

Lundbeck has entered a license agreement for the development and commercialisation of escitalopram in Japan with Mochida.

Mochida has signed an agreement to co-market escitalopram in Japan with Mitsubishi Tanabe Pharma Corporation.

Release no 405 - Positive pivotal results on escitalopram in Japan

 

Nalmefene is a specific opioid receptor antagonist.

Partner
Biotie Therapies Corp
http://www.biotie.com

Nalmefene is the first and only drug aimed at being indicated for the reduction of alcohol consumption in alcohol dependent patients with harmful consumption level. Lundbeck will position nalmefene as the drug of choice for patients who want to reduce their alcohol intake and where total abstinence is an unacceptable or un-needed treatment goal.

• Around 60 million EU citizens consumed alcohol in 2009 in a harmful or hazardous way
• Up to 15% of worldwide disease burden is attributable to alcohol consumption
• Only 1-2% receive treatment at some point in time
• Current treatments have maintained abstinence as the treatment goal and 50–75% of patients relapse within the first 12 months
• The harm of alcohol consumption hits broad and wide affecting drinkers, families, workplaces and society as a whole

(Sources: WHO, Health-EU)

Nalmefene is currently undergoing clinical phase III trials, which consists of three studies with a total of ~1,850 patients conducted in Europe.

For more information and study locations, please visit www.clinicaltrials.gov. 

About Clobazam
As a 1,5-benzodiazepene, clobazam has a distinctive chemical structure with associated unique properties when compared with other currently available benzodiazepines. It was initially developed to decrease the adverse effects seen with 1,4-benzodiazepines while still maintaining efficacy.  Clobazam in animal models works both by intensifying gamma-aminobutyric acid (GABA)-mediated inhibitory effects and by increasing activity of glutamate transporters.

Currently, clobazam is widely available worldwide with approvals in more than 100 countries for various uses in both children and adults, including the treatment of epilepsy and anxiety. Though not currently approved for any use in the U.S. the current clinical development program to gain U.S. Food and Drug Administration (FDA) approval for clobazam as adjunctive treatment for patients with LGS.

In previous studies clobazam was shown to be well tolerated in patients with LGS and met the primary endpoint in a Phase II dose range finding study of a significant reduction in drop (or atonic) seizures compared to baseline.  Drop seizures are the most debilitating of the LGS seizures types, which can result in severe trauma to the brain and body.

For more information and study locations, please visit www.clinicaltrials.gov. 

About Lennox-Gastaut Syndrome (LGS)
Lennox-Gastaut syndrome is a rare and debilitating form of epilepsy that frequently persists into adulthood1.  This form of catastrophic epilepsy, characterized by several seizure types, represents up to 10 percent of all childhood epilepsies2 and onset typically occurs between three and 10 years of age.  Drop attacks are frequent in LGS and responsible for most injuries associated with falls. Up to 90 percent of children with LGS are affected by mental retardation and these children commonly experience behavioral and sleep disturbances as well3.

1. Beaumanoir A, Blume, W. The Lennox-Gastaut Syndrome- Symptomatology During the Seizure Disorder. In: J. Roger MB, C. Dravet, P. Genton, C.A. Tassinari, & P. Wolf, ed. Epileptic Syndromes in Infancy, Childhood, and Adolescence 3rd ed. London: John Libbey & Co., Ltd. 2002:113-135.
    
2. Markand ON. Lennox-Gastaut syndrome (childhood epileptic encephalopathy). J Clin Neurophysiol. 2003;20:426-441.
    
3. Crumrine PK. Lennox-Gastaut syndrome. J Child Neurol. 2002;17 Suppl 1:S70-75.
   

For more information and study locations, please visit www.clinicaltrials.gov

Lu AA21004 has demonstrated in preclinical models that it provides enhanced efficacy and available clinical data show encouraging results for the potential efficacy and the tolerability profile of Lu AA21004:

• A European based 560-patient placebo-controlled MDD study shows statistical significance on the primary efficacy endpoint across all tested doses.
• Additionally a 639-patient relapse prevention study shows statistical significance in maintenance of efficacy in long-term treatment of MDD.
• Supportive study shows separation from placebo with 5 and 10 mg doses.
• Finally, the proof of concept study (clinical phase II) shows statistical significance on all tested doses

Lu AA21004 is an investigational multi-modal antidepressant that combines two pharmacological modes of action; reuptake inhibition and receptor activity. In vitro studies have shown that Lu AA21004 is a 5-HT₃, 5-HT₇ and 5-HT_1B receptor antagonist, 5‑HT_1A receptor agonist and 5-HT transporter inhibitor. A number of investigations in vivo have demonstrated that Lu AA21004 increases extracellular monoamine (5-HT, noradrenaline and dopamine) and acetylcholine and histamine levels in specific areas of the brain. All of these activities are considered to be of clinical relevance and potentially involved in the mechanism of action of Lu AA21004.

Lu AA21004 has demonstrated a low drug-drug interaction potential. It is extensively metabolized in the liver and the absorption of Lu AA21004 is independent of food intake.

The symptoms of depression can be chronic or recurrent, and impact patients both mentally and physically, yet it is still under-recognised and undertreated. Symptoms can include feelings of sadness, anxiety, loss of interest in activities, decreased energy, impaired sleep, impaired concentration, hopelessness, guilt, persistent physical symptoms such as pain and digestive disorders, and in more sever cases, suicidal thoughts and suicidal attempts.

 

About I.V. Carbamazepine
IV carbamazepine is a novel formulation of the widely used oral antiepileptic drug (AED) carbamazepine. As the potential first and only injectable form of the drug, IV carbamazepine is an important alternative for patients with epilepsy who may be hospitalized or otherwise temporarily unable to take oral carbamazepine. This clinical trial is designed to evaluate the bioequivalence of the intravenous doses with oral doses as well as assess the safety, tolerability and pharmacokinetics of IV carbamazepine relative to orally administered carbamazepine.

IV Carbamazepine as an oral preparation has a well-established therapeutic profile with nearly 40 years of clinical use in the United States and around the world. It is used in the management of complex partial seizures, as an adjunct in some patients with secondary or partial epilepsy (epilepsy originating in one area of the brain) with complex symptomatology or secondarily generalized seizures (partial seizures followed by epileptic activity in the entire brain) when administered in combination with other antiepileptic drugs (AEDs). It has also been found useful as an alternative medication in patients with generalized tonic-clonic seizures (the most common type of generalized seizures) who are experiencing marked side effects or fail to respond to other anticonvulsants.

About Epilepsy
According to the Epilepsy Foundation, there are approximately 2.7 million adults with epilepsy in the United States, making it the third most common neurological disorder in adults after Alzheimer's disease and stroke. Epilepsy is a neurological condition affecting the nervous system that produces seizures-which are sudden surges of electrical activity in the brain that usually affect how a person feels or acts. Some seizures can hardly be noticed, while others are totally disabling. The seizures in epilepsy may be related to a brain injury or genetic tendency, but most of the time the cause is unknown.

For more information and study locations, please visit www.clinicaltrials.gov. 

Desmoteplase is a novel, highly fibrin-specific thrombolytic agent in phase III of clinical development. In 2009, 2 large trials (DIAS-3 and DIAS-4) were started (www.clinicaltrials.gov: NCT00790920 & NCT00856661), and the results of these studies will determine whether desmoteplase will gain marketing authorization as a safe and effective treatment for patients with acute ischaemic stroke. Filing with health authorities is estimated in 2012. The Danish pharmaceutical company, H. Lundbeck A/S, owns the worldwide rights to desmoteplase.

Mode of action
Desmoteplase is a chemical found in the saliva of vampire bats that has the effect of catalysing the conversion of plasminogen to plasmin, which is the enzyme responsible for breaking down fibrin blood clots.

Discovery of desmoteplase
As early as in 1932, it was known that the saliva of the vampire bat (Desmodus rotundus) leads to interference with the haemostatic mechanism of the host animal [1]. In 1991, the DNA coding of 4 plasminogen activators present in the saliva of the vampire bat was completed [2]. Of the 4 plasminogen activators, recombinant Desmodus rotundus salivary plasminogen activator alpha 1 (rDSPAα1; desmoteplase) was investigated further [2].

Chemical structure
The structure of desmoteplase is similar to rtPA (alteplase), but it does not contain the plasmin-sensitive cleavage site and the lysine-binding Kringle 2 domain. As a result, desmoteplase, in comparison to rtPA, has high fibrin selectivity (100,000- v. 550-fold increase in catalytic activity), an absence of neurotoxicity, and no apparent negative effect on the blood-brain barrier. Desmoteplase also has a half-life of about 4 hours [3]; rtPA (alteplase) has a terminal plasma half-life of about 5 minutes.

Desmoteplase in Acute Ischaemic Stroke (DIAS) clinical trial program
The 2 phase II trials DIAS and DEDAS indicated that when intravenous desmoteplase was administered 3 to 9 hours after onset of ischaemic stroke symptoms, it was associated with a high rate of reperfusion and a low rate of symptomatic intracranial haemorrhage at doses up to 125 µg/kg. In the subsequent DIAS-2 trial, the same benefit could not be shown [6]. This could be explained by the inclusion of a substantial amount of patients with a mild stroke at baseline and small mismatch volumes associated with no vessel occlusion. Post hoc analyses of the DIAS-2 data showed that when patients had a proximal cerebral vessel occlusion or high-grade stenosis on baseline angiography, then a positive response for desmoteplase was shown [6].

In 2009, the DIAS-3 and DIAS-4 phase III trials started, each planning to enrol 400 patients worldwide who had had an acute ischaemic stroke. Participants will be treated with desmoteplase as an intravenous bolus dose of 90 µg/kg within 3 to 9 hours after stroke symptom onset. Patients are selected with occlusion or high-grade stenosis (TIMI 0-1) in proximal cerebral arteries as assessed by magnetic resonance or computed tomography angiography. Wherever possible, additional perfusion-weighted imaging and diffusion-weighted imaging assessments will be done.

The outcomes of DIAS-3 and DIAS-4 studies will tell whether desmoteplase is a breakthrough treatment for acute ischaemic stroke.

Read more
ClinicalTrials.gov (DIAS-3)
ClinicalTrials.gov (DIAS-4) 

References
1. Hawkey C. Inhibitor of platelet aggregation present in saliva of the vampire bat Desmodus rotundus. Br J Haematol.1967;13(6):1014-20.

2. Schleuning WD. Vampire bat plasminogen activator DSPA-alpha-1 (desmoteplase): a thrombolytic drug optimized by natural selection. Haemostasis. 2001;31(3-6):118-122.

3. Paciaroni M, Medeiros E, Bogousslavsky J. Desmoteplase. Expert Opin Biol Ther. 2009;9(6):773-778.

4. Hacke W, Albers G, Al Rawi Y, et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005;36(1):66-73.

5. Furlan AJ, Eyding D, Albers G. W, et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke. 2006;37(5):1227-1231.

6. Hacke W, Furlan AJ, Al Rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2009(2):141-150.

Stroke is the third leading cause of death in the industrialised world behind heart disease and cancer. The treatment of acute stroke and its serious long-term disabilities currently present an extensive unmet need. The only drug currently approved for the treatment of acute ischaemic stroke must be administered within 3 hours after the onset of stroke symptoms, which limits the potential patient population that can safely benefit from the rapid dissolution of the blood clot and the restoration of
blood supply to the affected area of the brain.

For more information and study locations, please visit www.clinicaltrials.gov. 

Lu AA24530 was selected as a development candidate based on its convincing effect in preclinical animal models suggesting fast onset of action and increased efficacy in the treatment of depression.

In pre-clinical studies, Lu AA24530 has demonstrated activities as a monoamine enhancer with reuptake inhibition at monoamine transporters, and antagonist activity at 5-HT3  and 5-HT2c 

Depression is a disease that affects a large proportion of the population, and it is also one of the most disabling diseases.

Common symptoms of depression are:
• Low mood
• Loss of pleasure or interest
• Loss of energy or increased tiredness

For more information and study locations, please visit www.clinicaltrials.gov. 

Zicronapine (previously known as Lu 31-130) is in clinical development for the treatment of psychosis on the basis of pharmacological data indicating antipsychotic activity combined with a reduced side-effect liability in vivo. Zicronapine is an atypical antipsychotic potentially capable of treating different psychotic symptoms.

Schizophrenia is a severe, disabling and, most often, chronic brain disorder with a considerable impact on the patients' quality of life. Furthermore, schizophrenia affects the patients' family, service systems and society as a whole.

As a chronic illness its costs to society are persistent. Schizophrenia is prevalent among a relatively small group of the population, but not least owing to its serious nature, the disease places a disproportionately large economic burden upon society.

For more information and study locations, please visit www.clinicaltrials.gov. 

Lu AE58054 is a potent and selective so-called 5-HT6 receptor antagonist. The 5-HT6 receptor is primarily found in areas of the brain involved in cognition. Early trials have demonstrated that 5-HT6 could offer potential in the treatment of Alzheimer's disease, but also other diseases that may lead to cognitive disturbances.

 

Lu AA39959, invented by Lundbeck’s own scientists, modulates ion channels in the brain via a new mechanism of action. In preclinical models of schizophrenia, the compound has demonstrated a particularly convincing antipsychotic potential.

Schizophrenia is a severe, disabling and, most often, chronic brain disorder with a considerable impact on the patients' quality of life. Furthermore, schizophrenia affects the patients' family, service systems and society as a whole.

As a chronic illness its costs to society are persistent. Schizophrenia is prevalent among a relatively small group of the population, but not least owing to its serious nature, the disease places a disproportionately large economic burden upon society.

For more information and study locations, please visit www.clinicaltrials.gov. 

Lu AA24493 is a novel cytoprotective compound. It is chemically modified EPO by carbamylation and does not bind to the erythropoietin receptor (EPOR) and is thereby without haematopoietic side-effects. Despite the lack of binding to EPOR, Lu AA24493 retains full cytoprotective properties, demonstrating that Lu AA24493 mediates its beneficial effects via a mechanism different from that of the classical EPOR.

Lu AA24493 is in clinical phase II in Friedreich's Ataxia.

Friedreich's ataxia is an inherited disease that causes progressive damage to the nervous system resulting in symptoms ranging from gait disturbance and speech problems to heart disease. It is named after the physician Nicholaus Friedreich, who first described the condition in the 1860s. "Ataxia," which refers to coordination problems such as clumsy or awkward movements and unsteadiness, occurs in many different diseases and conditions. The ataxia of Friedreich's ataxia results from the degeneration of nerve tissue in the spinal cord and of nerves that control muscle movement in the arms and legs. The spinal cord becomes thinner and nerve cells lose some of their myelin sheath — the insular covering on all nerve cells that helps conduct nerve impulses.

Friedreich's ataxia, although rare, is the most prevalent inherited ataxia, affecting about 1 in every 50,000 people in the Caucasian population. Males and females are affected equally.

As with many degenerative diseases of the nervous system, there is currently no cure or effective treatment for Friedreich's ataxia. However, many of the symptoms and accompanying complications can be treated to help patients maintain optimal functioning as long as possible.


Lundbeck is also conducting clinical phase I studies with Lu AA24493 in ischemic stroke.

Lu 02-750 is a dopaminergic agent acting on brain areas affected in Parkinson’s disease. In animal models, the compound has demonstrated very convincing effects as compared to conventional treatments. Expectations are that the compound can offer Parkinson’s patients a new and higher level of disease control.

Lu 02-750 has been discovered in close collaboration with Professor Håkan Wikström, Groningen University and Axon Biochemicals B.V.

Parkinson's disease is an age-related degenerative disorder of the brain. Symptoms can include tremor, stiffness, slowness of movement and impaired balance. An estimated four million people worldwide suffer from the disease, which usually affects people over the age of 60.

Lu AE04621 is a dopaminergic agent acting on brain areas affected in Parkinson’s disease. In animal models, the compound has demonstrated very convincing effects as compared to conventional treatments. Expectations are that the compound can offer Parkinson’s patients a new and higher level of disease control.

LUAE04621 is fully developed by Lundbeck.

Parkinson's disease is an age-related degenerative disorder of the brain. Symptoms can include tremor, stiffness, slowness of movement and impaired balance. An estimated four million people worldwide suffer from the disease, which usually affects people over the age of 60.